chr19-50417923-AC-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2
The NM_002691.4(POLD1):βc.3305delβ(p.Pro1102LeufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,608,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. P1101P) has been classified as Likely benign.
Frequency
Consequence
NM_002691.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.3305del | p.Pro1102LeufsTer22 | frameshift_variant | 27/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.3305del | p.Pro1102LeufsTer22 | frameshift_variant | 27/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000464 AC: 7AN: 150942Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000208 AC: 5AN: 240886Hom.: 0 AF XY: 0.00000763 AC XY: 1AN XY: 131074
GnomAD4 exome AF: 0.0000261 AC: 38AN: 1457798Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15AN XY: 724982
GnomAD4 genome AF: 0.0000464 AC: 7AN: 150942Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2AN XY: 73616
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2023 | Frameshift variant predicted to result in abnormal protein length as the last 6 amino acids are replaced with 21 different amino acids in a gene for which loss-of-function is not an established mechanism of disease; Observed in patients with pediatric leukemia, osteosarcoma, breast, or lung cancers (Lu et al., 2015; Alsultan et al., 2020; Mur et al., 2020; Zhang et al., 2015; Mirabello et al., 2020); This variant is associated with the following publications: (PMID: 32359129, 26689913, 32191290, 32792570, 26580448, 36451132) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 15, 2018 | - - |
Colorectal cancer, susceptibility to, 10 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 21, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change results in a frameshift in the POLD1 gene (p.Pro1102Leufs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the POLD1 protein and extend the protein by 15 additional amino acid residues. This variant is present in population databases (rs761614971, gnomAD 0.01%). This frameshift has been observed in individual(s) with acute lymphoblastic leukemia, breast cancer, and/or osteosarcoma (PMID: 32191290, 32359129, 32792570). ClinVar contains an entry for this variant (Variation ID: 408095). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 12, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 23, 2019 | The c.3305delC variant, located in coding exon 26 of the POLD1 gene, results from a deletion of one nucleotide at nucleotide position 3305, causing a translational frameshift with a predicted alternate stop codon (p.P1102Lfs*22). Frameshifts are typically deleterious in nature; however, this frameshift, which occurs at the 3' terminus of POLD1, is not expected to trigger nonsense-mediated mRNA decay and results in the elongation of the protein by 14 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at